Although several novel therapeutic approaches have been developed for treatment of germinal center B-cell lymphoma, overall, survival has not yet been significantly improved. One strategy with limited morbidity and mortality that has the potential to impact on survival is the generation of anti-lymphoma T-cell immunity. The natural history of FL with its regression and remissions has been thought to be associated with T-cell immunity. Vaccination of follicular lymphoma patients with idiotype protein results in durable clinical responses in some patients and has been associated with molecular remission in others. Preliminary evidence presented in Project 4 suggests that patients with diffuse large B-cell lymphoma who have enjoyed long-term disease free survival express genes that are associated with an immune phenotype. We therefore hypothesize that the status of anti-lymphoma T-cell immunity contributes to the regression and/or progression observed in germinal center B-cell lymphoma. To investigate the validity of these hypotheses as well as to attempt to improve outcome, we propose two specific aims. First, we will attempt to determine whether T-cell Immunity contributes to the control of follicular lymphoma in vivo and, if so, can we identify those lymphoma-associated antigens that are responsible for tumor control or regression. These studies will address whether: 1) unique lymphoma candidate antigens can be identified through genomic screening; 2) T-cells directed against these antigens can be detected in vivo, and 3) regression or progression are associated with the presence and magnitude of T-cell immunity directed against one or more of these antigens. Second, can we generate clinically significant autologous T-cell immunity to germinal center B-cell lymphoma by either vaccination with ex vivo altered lymphoma cells or with universal tumor associated antigens. These studies will address whether: 1) activated lymphoma cells can be used to induce immunity, 2) lymphoma patients are immunocompetent and, if not, can we correct it, and 3) whether we can generate significant anti-lymphoma T-cell immunity by immunizing with novel universal tumor antigens. Project 5 is highly collaborative with Project 4 and the Clinical, Pathology, Biostatistics, and Genomic (DNA Microarray/Bioinformatics) Cores.